This invention relates to a tissue plasminogen activator solution and method of preparation. More particularly, the invention concerns the enhancement of the solubility of tissue plasminogen activator in aqueous media without thereby causing a substantial loss in its potential biological activity upon administration.
Tissue plasminogen activator (t-PA) is a proteinaceous material, preferably glycosylated, which has thrombolytic activity whereby it is therapeutically useful for the treatment of patients suffering from a thrombosis or blood clot. The t-PA is generally administered parenterally, such as intravenously, in the form of an aqueous solution of the drug. The solution needs to be physiologically acceptable so that in addition to delivery of the desired therapeutic component to the patient the solution does not otherwise adversely affect the patient's electrolyte and volume balance. The aqueous medium for the t-PA thus usually comprises normal physiologic saline (0.85% NaCl, 0.15M), pH 7-7.4.
One problem with t-PA, in general, is that it is not as readily soluble in aqueous media as optimally desired for certain indications such that a sufficient concentration of the drug can be administered rapidly to a patient in a reasonable volume of solution. For example, in order to provide t-PA in a potency sufficient for maximal efficacy, an excessive amount of saline solution may be required to dissolve the desired amount of t-PA with a result that upon administration it produces a disturbance in the patient's fluid volume or osmolality. Therefore, it would be desirable to enhance the solubility of t-PA so that the amount of administered solution containing the t-PA can be reduced.
Various attempts have been made heretofor to improve the solubility of t-PA in aqueous solution. Thus, pharmaceutically acceptable surface active agents such as the polyoxyethylene sorbitan monoesters, e.g. Tween.RTM. 80 (polysorbate 80), have been used for this purpose. Use of Tween 80 and elevation of the ionic concentration of the t-PA solution to 0.3M NaCl (hypertonic saline) has been used heretofor as disclosed by Weimar et al., The Lancet., Nov. 7, 1981, pp. 1018-1020, and Collen et al., Thrombo. Haemostas. 48, 294-296 (1982). So also, lysine, ornithine and salts thereof have been reported as useful for increasing the solubility of t-PA in aqueous solution as seen from U.S. Pat. No. 4,568,544.